Higher Dose of CAR-T May Improve Efficacy in Relapsed/Refractory CLL

A higher dose of anti-CD19 CAR-T resulted in similar toxicities, but higher ORR and longer PFS, compared with a lower dose in patients with relapsed/refractory CLL.

A lower
dose of anti-CD19 chimeric antigen receptor (CAR) T-cell (CAR-T) therapy
resulted in similar overall survival (OS) as a higher dose among patients with
relapsed/refractory chronic lymphocytic leukemia (CLL), according to data from
a phase 2 trial.

Previous
studies demonstrated that CAR T cells can have substantial activity in a subset
of patients with relapsed/refractory CLL. In the authors’ prior study, the
overall response rate (ORR) to anti-CD19 CAR T cells was 57%, with no clear
relationship to dose. The purpose of this study was to determine an optimal
dose for future clinical trials with anti-CD19 CAR T cells for the treatment of
relapsed/refractory CLL.

Prior to
the CAR-T infusion, patients were recommended to undergo lymphodepleting
chemotherapy using standard regimens, but this was not required.

The
primary endpoint was the proportion of patient who achieved a complete response
(CR) at the end of 3 months. Key secondary endpoints included progression-free
survival (PFS), OS, cytokine release syndrome (CRS), and toxicities.

At
infusion, the median age was 61 years, and 78% of patients were male. Mutated TP53
or deletion 17p was presented in 28%, and IHGV
status was mutated in 6%.

The ORR
for the entire cohort was 44%, including CR in 28% and partial response (PR) in
16%. In the high-dose group, the ORR was 53%, which included 37% who achieved a
CR and 16% who achieved a partial response (PR). In the low-dose group, the ORR
was 29%; however, 1 patient did not reach the prespecified dose.

During a
median follow-up of 31.5 months for the entire evaluable cohort, the median OS
was 64 months and the median PFS was 1 month. There was no difference in OS by
dose group, as the median was 64 months for the high-dose group and 68 months
for the low-dose group (P =.84).

OS and
PFS were longer among patients who achieved CR. The 36-month OS was 89% among
patients who achieved CR compared with 50% among patients who did not reach CR.
Among patients who achieved CR, the 36-month OS was similar at 62% and 60% for
patients in the low-dose and high-dose groups. The 36-month PFS was 7.7% for
the low-dose group and 26% in the high-dose group.

Among
all patients, CRS developed in 63%, including 24% who experienced grade 3 to
grade 4 CRS. By dose groups, CRS occurred in 39% of patients who received the
low dose and 72% of patients who received the high dose.

Acknowledging
that the small numbers in the study limited the statistical significance, the
authors concluded that these data suggest that “the higher target dose (5 x 108
CART-19) using an adaptive split-dosing strategy was safe and possibly more
effective than the lower dose.”

Based on this study, the authors also stated that “strategies to further increase the CR rate to CART cells in CLL are warranted and many be supported by optimization of dose and scheduling.”

Disclosure: Some of the authors
disclosed financial relationships with pharmaceutical and/or medical companies.
For a full list of disclosures, please refer to the original study.

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